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Trans-(±)-TTPG-B Attenuates Cell Cycle Progression and Inhibits Cell Proliferation on Cholangiocarcinoma Cells
Thidarath Rattanaburee1,2, Chompunud Chompunud Na Ayudhya1, Tienthong Thongpanchang3
1Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand.
Abstract:
This research aimed to determine the target protein and molecular mechanism of trans-(±)-kusunokinin ((±)-KU) derivatives (trans-(±)-ARC and trans-(±)-TTPG-B). Molecular docking was used to predict potential synthesized (±)-KU targets among 22 proteins. The (±)-TTPG-B bound HSP90α better than EC44, native (±)-KU and (-)-KU, and (±)-KU and (-)-ARC. In contrast, (-)-ARC bound PI3K more strongly than any other test compound. CSF1R and AKR1B1 were not supposed to be the target of (±)-TTPG-B and (±)-ARC, unlike native (±)-KU. The (±)-TTPG-B bound Tyr139 and Trp162 of HSP90α. Moreover, (-)-ARC bound PI3K via hydrogen bonds and π-π stacking at distinct amino acids, which was different from the other tested compounds. Using half of the IC50 concentration, (±)-TTPG-B, (±)-KU and (±)-ARC enhanced cell cycle arrest at the G0/G1 phase after 12 h and 24 h on KKU-M213 (CCA) cells. The (±)-TTPG-B showed a stronger inhibitory effect than (±)-ARC and (±)-KU on HSP90α, PI3K, HSP90β, c-Myc, AKT, MEK1, CyclinB1, CyclinD1, and CDK1 for 24 and 48 h after treatment with the same concentration (0.015 µM). Thus, trans-(±)-TTPG-B, a newly synthesized compound, has pharmacological potential for development as a target therapy for CCA treatment.
Insights
Newly synthesized trans-(±)-TTPG-B targets HSP90α and PI3K, showing potential for cholangiocarcinoma (CCA) treatment. This compound effectively inhibits cancer cell proliferation by arresting the cell cycle.
Area of Science:
- Pharmacology
- Molecular Biology
- Medicinal Chemistry
Background:
- Kusunokinin derivatives are being investigated for therapeutic potential.
- Understanding the molecular targets and mechanisms of action is crucial for drug development.
Purpose of the Study:
- To identify the target proteins and elucidate the molecular mechanism of trans-(±)-kusunokinin ((±)-KU) derivatives, specifically trans-(±)-ARC and trans-(±)-TTPG-B.
- To evaluate the potential of trans-(±)-TTPG-B as a therapeutic agent for cholangiocarcinoma (CCA).
Main Methods:
- Molecular docking simulations were performed to predict potential protein targets among 22 candidates.
- In vitro assays were used to assess the binding affinities and inhibitory effects on target proteins and cancer cell lines.
- Cell cycle analysis was conducted to evaluate the impact of the compounds on cancer cell proliferation.
Main Results:
- Trans-(±)-TTPG-B exhibited strong binding to Heat Shock Protein 90 alpha (HSP90α), while trans-(±)-ARC showed higher affinity for Phosphoinositide 3-kinase (PI3K).
- Both compounds, along with (±)-KU, induced cell cycle arrest at the G0/G1 phase in KKU-M213 (CCA) cells.
- Trans-(±)-TTPG-B demonstrated superior inhibitory effects on multiple key proteins involved in cancer progression, including HSP90α, PI3K, and cell cycle regulators.
Conclusions:
- Trans-(±)-TTPG-B is identified as a promising therapeutic candidate for CCA due to its potent inhibition of key cancer-related targets.
- The findings provide a molecular basis for the development of novel targeted therapies for CCA.
